Biology Reference
In-Depth Information
compartments. Understanding its biology may identify targets for increasing
axonal trafficking. It is located at the most proximal part of the axon and plays
an important role in action potential initiation, but is also understood to
regulate the entry of proteins into the axon. It contains high densities of
voltage-gated Na
þ
(Nav) and K
þ
(Kv) channels, as well as dense clusters of
cell adhesion molecules such as neuronal cell adhesion molecule (NrCAM)
and neurofascin 186 (NF186), and the scaffolding proteins
b
IV spectrin
and ankyrin G (AnkG). During AIS assembly, AnkG is the first protein to be-
come stabilized at the AIS and tethers adhesion molecules and ion channels
with AnkG-binding domains (
Boiko et al., 2007; Dzhashiashvili et al.,
2007; Garrido et al., 2003; Hedstrom, Ogawa, & Rasband, 2008; Yang,
Ogawa, Hedstrom, &Rasband, 2007; Zhou et al., 1998
).
b
IV spectrin binds
to AnkG and the actin cytoskeleton (
Yang et al., 2007
), while NF186 assem-
bles the AIS proteins to a specialized brevican-containing ECM that
surrounds the AIS (
Hedstrom et al., 2007
). AnkG is considered the central
organizer of theAIS, and as such it plays an important role inmaintaining neu-
ronal polarity. Loss of AnkG in cultured neurons prevents the localization of
other AIS molecules and causes axons to acquire dendritic features such as
spines and postsynaptic densities, but this does not occur after loss of
NF186, NrCAM, Nav channels, or
b
IV spectrin (
Hedstrom et al., 2008
).
In vivo
, however, NF186 is required for AIS maintenance and function
(
Zonta et al., 2011
), andmice lacking
b
IV spectrin have reducedNav channel
densities and membrane abnormalities (
Yang, Lacas-Gervais, Morest,
Solimena, & Rasband, 2004
). In mice with a cerebellum-specific AnkG de-
ficiency, axons acquired characteristics of dendrites (
Sobotzik et al., 2009
)
similar to the results of AnkG knockdown in cultured neurons. Interestingly,
however, Purkinje neurons in AnkG-deficient mice are still polarized with
normal axon trajectories through the granule cell layer (
Sobotzik et al., 2009
).
How does the AIS preserve the polarized morphology of neurons? There
is evidence that the AIS prevents diffusion of proteins between the
somatodendritic and axonal compartments both on the surface and within
the axon. At the AIS membrane, diffusion of phospholipids is impeded
(
Kobayashi, Storrie, Simons, & Dotti, 1992; Nakada et al., 2003
), and the
lateral mobility of certain membrane proteins is reduced (
Winckler,
Forscher, & Mellman, 1999
). Within the axon, diffusion of large cytoplas-
mic proteins is restricted at the AIS indicating the existence of a cytoplasmic
transport filter, but there is also regulation of microtubule-based vesicular
transport of membrane proteins (
Song et al., 2009
). This study demonstrated
that transport of vesicles carrying the dendrite-targeting NMDA receptor
